EPAS1 is a member of the HIF (hypoxia inducible factor) gene family. Also known as Hif2 alpha, EPAS1 encodes half of a transcription factor involved in the induction of genes regulated by oxygen, and which is induced as oxygen levels fall (a condition known as hypoxia).
Certain variants of this gene provide protection for people living at high altitude. However, at low altitude, over-expression of wild-type (WT) EPAS1 is associated with increased hypertension and stroke, and with symptoms similar to mountain sickness. Mutations in this gene are also associated with erythrocytosis familial type 4 and pulmonary hypertension. EPAS1 can also cause excessive production of red blood cells, leading to inhibited reproductive abilities or even death.
EPAS1 is also required for or enhances the expression of various genes involved in an assortment of diseases, including tumor progression. For example, EPAS1 plays an important role in the progression of uveal melanomas, possibly by promoting the autocrine loop VEGF-pVEGFR2/KDR, and by enhancing the expression of LDHA, thus conferring a growth advantage.
EPAS1 is also involved in or upregulates expression of many factors, including: c-Myc (which favors cell proliferation, transformation, neoplasia and tumorigenesis, and which is highly expressed in most cancers): Interleukin 8 (a proinflammatory mediator, e.g., in gingivitis and psoriasis); SP-1 (a transcription factor involved in IL-8 regulation and a coactivator of c-Myc); LDH5 (which is linked with tumor necrosis and increased tumor size); and LANA (Latency Associated Nuclear Antigen, which is associated with Kaposi's sarcoma-associated Herpesvirus). In addition, HIF (hypoxia induced factor) activity is involved in angiogensis required for cancer tumor growth. EPAS1 is also involved in several other diseases, including inflammation, including chronic inflammation, neovascular diseases, rheumatoid arthritis, renal cancer, clear cell renal cell carcinoma (and metastases of this and other cancers), melanoma, uveal melanoma, chondrosarcoma, and multiple myeloma.
There thus exists the need for treatments related to these and other EPAS1-related diseases.